CN105916836A

CN105916836A - Production method for 2-fluoro-4-borono-l-phenylalanine, and precursor of 2-fluoro-4-borono-l-phenylalanine

Info

Publication number: CN105916836A
Application number: CN201480069329.1A
Authority: CN
Inventors: 竹中宏志; 大田洋郎; 大田洋一郎; 田口祐辅; 上田沙悠里; 石野祐子; 吉川智裕; 中岛秀纪; 上原幸树; 切畑光统
Original assignee: Stellar International Inc; Osaka Prefecture University PUC
Current assignee: Public University Legal Person Osaka; Stellar International Inc
Priority date: 2013-12-17
Filing date: 2014-12-16
Publication date: 2016-08-31
Anticipated expiration: 2034-12-16
Also published as: JPWO2015093469A1; US20160311836A1; KR102137214B1; US10344042B2; CA2933846C; TWI640496B; KR20160098449A; CN105916836B; US20170283441A1; US10005794B2; JP6455572B2; AU2014367825B9; AU2014367825B2; SG11201604993WA; EP3085687A1; JP2018024668A; EP3085687B1; MY183427A; CA2933846A1; RU2668166C1

Abstract

The present invention involves preparing compounds represented by the formula. In the formula: R1 represents a Br group, an iodine group, a Cl group, an NO2 group, or an NH2 group; R2 represents a halogen group, an NO2 group, an NH2 group, Sn(R6)3, N=N-NR7R8, OSO2R9, N R10R11, phenyliodonium, a heterocyclic group iodine, boric acid, or a borate ester; R30 represents a protective group PG1; R40 or R50 represent hydrogen, a protective group PG2, or C6H5(C6H5)C=N, wherein NR40R50 are together.

Description

The manufacture method of 2-fluoro-4-borono-L-phenylalanine and 2-fluoro-4-dihydroxy boron The precursor of base-L-phenylalanine

Technical field

The present invention relates to 2-fluoro-4-borono-L-phenylalanine (fluorination BPA) (BPA:4-BPA, Manufacture method 4-Boronophenylalanine) and precursor thereof.

Background technology

Now, positron emission computerized tomography method (Positron Emission Tomography:PET) because of its principle, Enjoy gaze at as excellence highly sensitive, quantitative, the easy technology of image conversion, be widely used.Owing to diagnosis using Half-life of PET diagnostic reagent (tracer) short, micro-administration, so the radiation to organism is few, is the inspection of low wound Method, this is also considered as the big advantage of PET.And, even if PET is to CT (computed tomography), MRI (NMR (Nuclear Magnetic Resonance)-imaging) The tumor being difficult to judge also is able to carry out the picture appraisal of cancerous tissue with high sensitivity.

The boronated amino acid BPA used to the boron medicament as BNCT (boron neutron capture therapy method) imports¹⁸F-fluorine is former Son¹⁸F labelling BPA was crossed the molecular probe (non-patent literature 1) developing into PET in 1991 by stone.All the time, this spy is used The utilization that pin is carried out¹⁸The PET of F labelling BPA checks it is one of important technology supporting BNCT.That is, at clinical, research field, root According in advance object is measured¹⁸F BPA PET image, it is possible to obtain the internal Assembled distribution of BPA, tumor tissues/normal structure There is ratio information such as (T/N ratios), the therapeutic effect of BNCT can be supposed based on these information in advance, formulate research or treatment side Case.

In the synthetic method that stone crosses, BPA is directly fluorinated and obtains¹⁸F labelling BPA, will¹⁸F⁺As electrophilic reagent. It is used in cyclotron the deuterium (D) accelerated and is prepared by neon (Ne)¹⁸F gas so that it is by being filled with the post of sodium acetate, be converted into CH₃COO^-18F⁺After, its bubbling is imported the trifluoroacetic acid solution of BPA, it is achieved target¹⁸The synthesis of F labelling BPA.

Additionally, conduct¹⁸The synthetic method of F labelling BPA, Vahatalo et al. also proposed and carries out such previous methods Part improves (non-patent literature 2).The method is to use the H that can obtain in a large number¹⁸F, via CH₃ ¹⁸F conduct¹⁸F₂Intermediate Method, it may be assumed that make H₂ ¹⁸O irradiation proton [¹⁸O(p,n)¹⁸F react] obtained by H¹⁸F and CH₃I reacts, and temporarily synthesizes CH₃ ¹⁸F, makes The CH obtained₃ ¹⁸C-F key is dissociated and becomes by F electric discharge¹⁸F₂, use¹⁸F₂, synthesize in the same manner as the synthetic method of Shi Du etc.¹⁸F labelling The method of BPA.

Prior art literature

Non-patent literature

Non-patent literature 1:Appl.Radiat.Isot., 42,325,1991.

Non-patent literature 2:J.Label.Compd.Radiopharm., 45,697,2002

Summary of the invention

But, utilize the synthetic method of existing Shi Du etc. to obtain¹⁸F labelling BPA, its intrinsic specific activity is low, and yield Seldom.Even if modification method, although obtain¹⁸The intrinsic specific activity of F labelling BPA uprises, but still is the state that yield is few.

It is an object of the invention to provide and can become for synthesizing¹⁸The new BPA derivant of the intermediate of F labelling BPA.

Manufacture the method for such new BPA derivant it addition, it is an object of the invention to provide and comprise and employ this Obtained by new BPA derivant¹⁸The manufacture method of the Fization BPA of F labelling BPA.

The present inventor etc. conduct in-depth research to solve above-mentioned problem, found that the new synthesis method of Fization BPA, Thus complete the present invention.

That is, the present invention relates to the compound that a kind of following formula represents:

Wherein, R¹Represent bromo, iodo, chloro, nitro or amino, R²Represent halogen radical, nitro, amino, Sn (R⁶)₃, N=N-NR⁷R⁸、OSO₂R⁹、NR¹⁰R¹¹, replace or unsubstituted phenyl-iodide, replacement or unsubstituted heterocyclic radical iodine or Boric acid (B (OH)₂) or borate, this borate selected from pinacol, 2，2-dimethyl-1，3-propanediol, N methyldiethanol amine, Any one in 1,8-diaminonaphthalene, N-methyliminodiacetic acid, 1,1,1-trihydroxy methyl ethane and catechol is (wherein, R⁶Represent alkyl or the benzyl of carbon number 1～7；R⁷And R⁸Identical or different, represent hydrogen, the alkyl of carbon number 1～7, quilt The alkyl of the carbon number 1～7 of halogen substiuted, any substituted phenyl, or form the ring with 3～7 atoms together with N Structure；R⁹The alkyl representing carbon number 1～7, the alkyl of carbon number 1～7 being optionally substituted by halogen or any substituted benzene Base；R¹⁰And R¹¹Identical or different, represent carbon number 1～7 alkyl, be optionally substituted by halogen carbon number 1～7 alkyl, appoint Anticipate substituted phenyl, or form the ring structure with 3～7 atoms together with N)；R³Represent hydrogen, ethyl, the tert-butyl group or Benzyl, R⁴Or R⁵Represent hydrogen, benzyloxycarbonyl or tert-butoxycarbonyl, or NR independently⁴R⁵Overall expression C₆H₅ (C₆H₅) C=N,

(wherein, not including following situation: 1) R³、R⁴And R⁵All hydrogen, and R²Situation for chloro；2)R³、R⁴And R⁵ All hydrogen, R²For bromo, and R¹For the situation of any one in bromo, chloro, nitro or amino；3)R³、R⁴And R⁵All Hydrogen, R²For iodo, and R¹For the situation of any one in chloro or nitro；

4)R³For hydrogen, R²For chloro, and R¹For in chloro, bromo or nitro any one, R⁴Or R⁵In any one is hydrogen Situation；

5)R³For hydrogen, R²For bromo, and R¹For chloro, R⁴Or R⁵In any one is the situation of hydrogen；

6)R⁴And R⁵For hydrogen, R²For chloro, and R¹Situation for nitro；

7)NR⁴R⁵Overall expression C₆H₅(C₆H₅) C=N, and R²For fluorine-based situation；

8)R¹For chloro, R²For fluorine-based, R⁴And R⁵For hydrogen, and R³Situation for ethyl).

In a mode, in above-claimed cpd, preferably

R¹Represent bromo, iodo, chloro, nitro or amino, R²Represent halogen radical, nitro, amino, Sn (R⁶)₃, N= N-NR⁷R⁸、OSO₂R⁹、NR¹⁰R¹¹, replace or unsubstituted phenyl-iodide, replacement or unsubstituted heterocyclic radical iodine or boric acid (B (OH)₂) or borate, this borate selected from pinacol, 2，2-dimethyl-1，3-propanediol, N methyldiethanol amine, 1,8-bis- Any one (wherein, R in amino naphthalenes, N-methyliminodiacetic acid, 1,1,1-trihydroxy methyl ethane and catechol⁶Represent The alkyl of carbon number 1～7 or benzyl；R⁷And R⁸Identical or different, represent hydrogen, the alkyl of carbon number 1～7, taken by halogen The alkyl of the carbon number 1～7 in generation, any substituted phenyl, or form the ring structure with 3～7 atoms together with N； R⁹The alkyl representing carbon number 1～7, the alkyl of carbon number 1～7 being optionally substituted by halogen or any substituted phenyl；R¹⁰ And R¹¹Identical or different, represent carbon number 1～7 alkyl, be optionally substituted by halogen carbon number 1～7 alkyl, arbitrarily replace Phenyl, or form the ring structure with 3～7 atoms together with N) (wherein, R¹And R²In either one is necessary for bromine Base, iodo or chloro)；R³Represent hydrogen, ethyl, the tert-butyl group or benzyl, R⁴Or R⁵Represent hydrogen, benzyloxy carbonyl independently Base or tert-butoxycarbonyl, or NR⁴R⁵Overall expression C₆H₅(C₆H₅) C=N,

4)R³For hydrogen, R²For chloro, and R¹For the situation of any one in chloro, bromo or nitro；

6)R⁴And R⁵For hydrogen, R²For chloro, and R¹Situation for nitro；

In a mode, in above-claimed cpd, preferably

R¹Represent bromo, iodo, chloro, nitro or amino, R²Represent halogen radical, nitro, amino, Sn (R⁶)₃, N= N-NR⁷R⁸、OSO₂R⁹、NR¹⁰R¹¹, replace or unsubstituted phenyl-iodide, replacement or unsubstituted heterocyclic radical iodine or boric acid (B (OH)₂) or borate, this borate selected from pinacol, 2，2-dimethyl-1，3-propanediol, N methyldiethanol amine, 1,8-bis- Any one (here, R in amino naphthalenes, N-methyliminodiacetic acid, 1,1,1-trihydroxy methyl ethane and catechol⁶Represent The alkyl of carbon number 1～7 or benzyl；R⁷And R⁸Identical or different, represent hydrogen, the alkyl of carbon number 1～7, taken by halogen The alkyl of the carbon number 1～7 in generation, any substituted phenyl, or form the ring structure with 3～7 atoms together with N； R⁹The alkyl representing carbon number 1～7, the alkyl of carbon number 1～7 being optionally substituted by halogen or any substituted phenyl；R¹⁰ And R¹¹Identical or different, represent carbon number 1～7 alkyl, be optionally substituted by halogen carbon number 1～7 alkyl, arbitrarily replace Phenyl, or form the ring structure with 3～7 atoms together with N) (wherein, R¹And R²In either one is necessary for bromine Base, iodo or chloro)；R³Represent hydrogen, ethyl, the tert-butyl group or benzyl, R⁴Or R⁵Represent hydrogen, benzyloxy carbonyl independently Base or tert-butoxycarbonyl, or NR⁴R⁵Overall expression C₆H₅(C₆H₅) C=N,

5)R³For hydrogen, R²For bromo, and R¹Situation for chloro；

6)R⁴And R⁵For hydrogen, R²For chloro, and R¹Situation for nitro；

Moreover, it relates to the manufacture method of compound that a kind of following formula represents,

(wherein, X represent F or¹⁸F, R³⁰、R⁴⁰And R⁵⁰With following R³⁰、R⁴⁰And R⁵⁰Identical, R¹⁵And R¹⁶(boron is former with B Son) together form the ring of the blocking group as B),

This manufacture method includes the operation of the compound using following formula to represent,

Wherein, R¹Represent bromo, iodo, chloro, nitro or amino, R²Represent halogen radical, nitro, amino, Sn (R⁶)₃, N=N-NR⁷R⁸、OSO₂R⁹、NR¹⁰R¹¹, replace or unsubstituted phenyl-iodide, replacement or unsubstituted heterocyclic radical iodine or Any one (wherein, R in boric acid or borate⁶Represent alkyl or the benzyl of carbon number 1～7；R⁷And R⁸It is identical or different, Represent hydrogen, the alkyl of carbon number 1～7, the alkyl of carbon number 1～7 being optionally substituted by halogen, any substituted phenyl, or The ring structure with 3～7 atoms is formed together with N；R⁹The alkyl representing carbon number 1～7, the carbon atom being optionally substituted by halogen The alkyl of several 1～7 or any substituted phenyl；R¹⁰And R¹¹Identical or different, represent the alkyl of carbon number 1～7, by halogen The element alkyl of substituted carbon number 1～7, any substituted phenyl, or form the ring knot with 3～7 atoms together with N Structure)；R³⁰Represent hydrogen or the blocking group PG of carboxyl¹, R⁴⁰Or R⁵⁰Represent hydrogen or the blocking group PG of amino independently², Or NR⁴⁰R⁵⁰Overall expression C₆H₅(C₆H₅) C=N).

It addition, in the present invention, relate to one¹⁸The manufacture method of F labelling BPA, including the compound using following formula to represent Operation,

(wherein, X represent F or¹⁸F, R³⁰、R⁴⁰And R⁵⁰With above-mentioned R³⁰、R⁴⁰And R⁵⁰Identical, R¹⁵And R¹⁶(boron is former with B Son) together form the ring of the blocking group as B).

The new compound of the present invention and manufacture method are particularly suitable for¹⁸The manufacture of F labelling BPA.

Detailed description of the invention

Synthesis¹⁸The existing method of F labelling BPA is the method being directly fluorinated by BPA, especially by inciting somebody to action¹⁸F is as parent Electrophile carries out electrophilic reaction and realizes.The present inventor etc. notice in such existing synthesis path, in convolution Preparation in accelerator¹⁸F₂The operation of gas, by obtain¹⁸F₂Gas is as F⁺The operation utilized etc. are respectively present problem, this Outward, owing to being mixed into¹⁹F₂The generation etc. of the product caused by molecule, finally gives¹⁸The intrinsic specific activity fall of F labelling BPA Low, and 1 synthesis can be used for PET diagnosis¹⁸F labelling BPA is the amount about several person-portion.The present invention's is new¹⁸F labelling BPA Synthetic method is entirely different with conventional method, is available¹⁸The synthetic method of F anion is few to the load of device, it is possible to close Become the fruitful amount of ratio synthetic method so far¹⁸F labelling BPA.

In the present invention, first find the manufacture method of new Fization BPA, particularly¹⁸The manufacture method of F labelling BPA.Additionally, Such new¹⁸In the manufacture method of F labelling BPA, obtain several new midbody compound.Utilize this new¹⁸F labelling The manufacture method of BPA, it is possible to easy and obtain with high yield¹⁸F labelling BPA.

In the present invention, here, Fization BPA refers to following compound

Or it is following as comprising¹⁸The term of F labelling BPA uses.Here,¹⁸F labelling BPA refers to following chemical combination Thing.

In the present invention, the new midbody compound that final offer is relevant to these Fization BPA compou nd synthesis.

In the present invention, the compound implication that new midbody compound represents with following formula is identical.

Wherein, R¹Represent bromo, iodo, chloro, nitro or amino, R²Represent halogen radical, nitro, amino, Sn (R⁶)₃, N=N-NR⁷R⁸、OSO₂R⁹、NR¹⁰R¹¹, replace or unsubstituted phenyl-iodide, replacement or unsubstituted heterocyclic radical iodine or Boric acid (B (OH)₂) or any one of borate, this borate is selected from pinacol, 2，2-dimethyl-1，3-propanediol, N-methyl Diethanolamine, 1,8-diaminonaphthalene, N-methyliminodiacetic acid, 1,1,1-trihydroxy methyl ethane and catechol (wherein, R⁶ Represent alkyl or the benzyl of carbon number 1～7；R⁷And R⁸Identical or different, represent hydrogen, the alkyl of carbon number 1～7, by halogen The element alkyl of substituted carbon number 1～7, any substituted phenyl, or form the ring knot with 3～7 atoms together with N Structure；R⁹The alkyl representing carbon number 1～7, the alkyl of carbon number 1～7 being optionally substituted by halogen or any substituted benzene Base；R¹⁰And R¹¹Identical or different, represent carbon number 1～7 alkyl, be optionally substituted by halogen carbon number 1～7 alkyl, appoint Anticipate substituted phenyl, or form the ring structure with 3～7 atoms together with N)；R³Represent hydrogen, ethyl, the tert-butyl group or Benzyl, R⁴Or R⁵Represent hydrogen, benzyloxycarbonyl or tert-butoxycarbonyl, or NR independently⁴R⁵Overall expression C₆H₅ (C₆H₅) C=N,

6)R⁴And R⁵For hydrogen, R²For chloro, and R¹Situation for nitro；

8)R¹For chloro, R²For fluorine-based, R⁴And R⁵For hydrogen, and R³Situation for ethyl)

Although being not particularly limited, but further preferably:

R¹Represent bromo, iodo, chloro, nitro or amino, R²Represent halogen radical, nitro, amino, Sn (R⁶)₃, N= N-NR⁷R⁸、OSO₂R⁹、NR¹⁰R¹¹, replace or unsubstituted phenyl-iodide, replacement or unsubstituted heterocyclic radical iodine or boric acid (B (OH)₂) or any one of borate, this borate is selected from pinacol, 2，2-dimethyl-1，3-propanediol, N-methyl diethanol Amine, 1,8-diaminonaphthalene, N-methyliminodiacetic acid, 1,1,1-trihydroxy methyl ethane and catechol (wherein, R⁶Represent carbon The alkyl of atomic number 1～7 or benzyl；R⁷And R⁸Identical or different, represent hydrogen, the alkyl of carbon number 1～7, be optionally substituted by halogen The alkyl of carbon number 1～7, any substituted phenyl, or form the ring structure with 3～7 atoms together with N；R⁹ The alkyl representing carbon number 1～7, the alkyl of carbon number 1～7 being optionally substituted by halogen or any substituted phenyl；R¹⁰With R¹¹Identical or different, the alkyl that represents carbon number 1～7, the alkyl, the most substituted of the carbon number 1～7 being optionally substituted by halogen Phenyl, or form the ring structure with 3～7 atoms together with N) (wherein, R¹And R²In either one be necessary for bromo, Iodo or chloro)；R³Represent hydrogen, ethyl, the tert-butyl group or benzyl, R⁴Or R⁵Represent independently hydrogen, benzyloxycarbonyl, Or tert-butoxycarbonyl, or NR⁴R⁵Overall expression C₆H₅(C₆H₅) C=N,

6)R⁴And R⁵For hydrogen, R²For chloro, and R¹Situation for nitro；

Additionally, in another way, preferably:

5)R³For hydrogen, R²For bromo, and R¹Situation for chloro；

6)R⁴And R⁵For hydrogen, R²For chloro, and R¹Situation for nitro；

Additionally, in another way, preferably:

R¹Represent bromo, iodo, chloro, nitro or amino, R²Represent halogen radical, nitro, amino, Sn (R⁶)₃, N= N-NR⁷R⁸、OSO₂R⁹、NR¹⁰R¹¹、I⁺R¹³、(R^14-)I⁺R¹³, or any one of boric acid or borate, this borate selected from frequency which Alcohol, 2,2-dimethyl-1,3-propylene glycol, N methyldiethanol amine, 1,8-diaminonaphthalene, N-methyliminodiacetic acid, 1,1, 1-trihydroxy methyl ethane and catechol (wherein, R⁶Represent methyl or normal-butyl；R⁷And R⁸Identical or different, represent hydrogen, first Base, ethyl, propyl group, butyl, heptyl, trifluoromethyl or any substituted phenyl, or formed together with N aziridine, Azetidine, pyrrolidine, piperidines；R⁹Represent methyl, ethyl, propyl group, butyl, heptyl, trifluoromethyl or the most substituted Phenyl；R¹⁰And R¹¹Identical or different, represent methyl, ethyl, propyl group, butyl, heptyl, trifluoromethyl or any substituted benzene Base, or form aziridine, azetidine, pyrrolidine, piperidines together with N；R¹³Represent C_1-6Alkyl-substituted phenyl, C_1-6 Alkoxy substituted phenyl or phenyl, or represent the 5～7 yuan of heterocyclic radicals comprising 1 in N, S or O or more than 2, R¹⁴Table Show halogen, Tetrafluoroboric acid alkali, nitrate-based, trifluoromethanesulfonic acid alkali, sulfonyloxy, tosyloxy or perchloric acid Alkali) (wherein, R¹And R²In either one is necessary for bromo, iodo or chloro)；R³Represent hydrogen, ethyl, the tert-butyl group or Person's benzyl, R⁴Represent hydrogen, R⁵Represent hydrogen, benzyloxycarbonyl or tert-butoxycarbonyl, or NR⁴R⁵Overall expression C₆H₅(C₆H₅) C=N (wherein, not including following 1)～8) situation: 1) R³、R⁴And R⁵All hydrogen, and R²Situation for chloro；2)R³、R⁴ And R⁵All hydrogen, R²For bromo, and R¹For the situation of any one in bromo, chloro, nitro or amino；3)R³、R⁴And R⁵Entirely Portion is hydrogen, R²For iodo, and R¹For the situation of any one in chloro or nitro；

4)R³For hydrogen, R²For chloro, and R¹(wherein, R is also included for the situation of any one in chloro, bromo or nitro⁴、 R⁵In any one is hydrogen, but R⁴、R⁵It is not all the situation of hydrogen)；

5)R³For hydrogen, R²For bromo, and R¹Situation for chloro (wherein, also includes R⁴、R⁵In any one is hydrogen, but R⁴、R⁵ It is not all the situation of hydrogen)；

6)R⁴And R⁵For hydrogen, R²For chloro, and R¹Situation for nitro；

In the new midbody compound of the present invention, particularly preferred following compound: R in above-claimed cpd¹Represent bromine Base, iodo or chloro, R²Represent Sn (R⁶)₃, N=N-NR⁷R⁸、OSO₂R⁹、NR¹⁰R¹¹、I⁺R¹³、(R^14-)I⁺R¹³, or boric acid Or pinacol, 2,2-dimethyl-1,3-propylene glycol, N methyldiethanol amine, 1,8-diaminonaphthalene, N-methyl-imino diethyl Acid, 1,1,1-trihydroxy methyl ethane, catechol any one.

In the new midbody compound of the present invention, particularly preferred R in above-claimed cpd²For iodo or bromo.

The new compound of the present invention does not limit, and is particularly preferably used as such as PET diagnostic reagent preparation intermediate Compound.

In the present invention, the compound that use following formula represents:

(wherein, R¹Represent bromo, iodo, chloro, nitro or amino, R²Represent halogen radical, nitro, amino, Sn (R⁶)₃, N=N-NR⁷R⁸、OSO₂R⁹、NR¹⁰R¹¹, replace or unsubstituted phenyl-iodide, replacement or unsubstituted heterocyclic radical iodine, boric acid Or any one (wherein, R of borate⁶Represent alkyl or the benzyl of carbon number 1～7；R⁷And R⁸Identical or different, represent Hydrogen, the alkyl of carbon number 1～7, the alkyl of carbon number 1～7 being optionally substituted by halogen, any substituted phenyl, or with N mono- Rise and form the ring structure with 3～7 atoms；R⁹Represent the alkyl of carbon number 1～7, the carbon number 1 being optionally substituted by halogen～ The alkyl of 7 or any substituted phenyl；R¹⁰And R¹¹Identical or different, represent the alkyl of carbon number 1～7, taken by halogen The alkyl of the carbon number 1～7 in generation, any substituted phenyl, or form the ring structure with 3～7 atoms together with N) (preferably R¹And R²In either one is necessary for bromo, iodo or chloro)；R³⁰Represent hydrogen or the blocking group of carboxyl PG¹, R⁴⁰Or R⁵⁰Represent hydrogen or the blocking group PG of amino independently², or NR⁴⁰R⁵⁰Overall expression C₆H₅(C₆H₅) C= N),

Can manufacture the compound that following formula represents:

(wherein, X represent F or¹⁸F, R³⁰、R⁴⁰And R⁵⁰With above-mentioned R³⁰、R⁴⁰And R⁵⁰Identical, R¹⁵And R¹⁶(boron is former with B Son) together form the ring of the blocking group as B).Thus obtained compound is used can the most finally to manufacture Fization BPA, particularly¹⁸F labelling BPA.

In the present invention, the compound using following formula to represent can manufacture¹⁸F labelling BPA,

Wherein, R¹Represent bromo, iodo, chloro, nitro or amino, R²Represent halogen radical, nitro, amino, Sn (R⁶)₃, N=N-NR⁷R⁸、OSO₂R⁹、NR¹⁰R¹¹, replace or unsubstituted phenyl-iodide, replacement or unsubstituted heterocyclic radical iodine, boric acid Or borate (particularly preferred pinacol, 2,2-dimethyl-1,3-propylene glycol, N methyldiethanol amine, 1,8-diaminonaphthalene, N- Methyliminodiacetic acid, 1,1,1-trihydroxy methyl ethane or catechol) any one (wherein, R⁶Represent carbon number The alkyl of 1～7 or benzyl；R⁷And R⁸Identical or different, represent that hydrogen, the alkyl of carbon number 1～7, the carbon that is optionally substituted by halogen are former The alkyl of subnumber 1～7, any substituted phenyl, or form the ring structure with 3～7 atoms together with N；R⁹Represent carbon The alkyl of atomic number 1～7, the alkyl of the carbon number 1～7 being optionally substituted by halogen or any substituted phenyl；R¹⁰And R¹¹Phase Same or different, represent the alkyl of carbon number 1～7, the alkyl of carbon number 1～7 being optionally substituted by halogen, any substituted benzene Base, or form the ring structure with 3～7 atoms together with N) (wherein, R¹And R²In either one is necessary for bromo, iodine Base or chloro)；R³⁰Represent hydrogen or the blocking group PG of carboxyl¹, R⁴⁰Or R⁵⁰Represent hydrogen or the guarantor of amino independently Protect group PG², or NR⁴⁰R⁵⁰Overall expression C₆H₅(C₆H₅) C=N).

In this specification, " forming the ring structure with 3～7 atoms together with N " refers to saturated or undersaturated has Carbon and the ring of nitrogen.Do not limit, piperidines, piperazine, pyrrolidine, pyridine, pyrimidine, pyrazine, pyrazoles and imidazoles can be illustrated.

In this specification, heterocyclic radical refers to have the saturated or undersaturated ring structure that has of atom beyond carbon and carbon Group, particularly preferred thienyl, furyl, pyridine radicals, piperidyl or piperazinyl etc..

R³⁰Represent hydrogen or the blocking group PG of carboxylic acid¹, here, PG¹It is not particularly limited, represents those skilled in the art The blocking group of known whole carboxylic acid.Such as, Greene watts can be enumerated and write " the blocking group the (the 3rd in organic synthesis Version) (Protective groups in organic synthesis) " (U.S., Wiley-Interscience company) middle note The blocking group carried.Representational is that available ester condensation condition, alkylation conditions become ester type and protect.PG¹In, example As, the aromatic groups such as carbon number 1～the alkyl of 7, benzyl can be enumerated.That is, methyl, ethyl, n-pro-pyl, isopropyl can be enumerated The alkyl such as base, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl, benzyl, to methoxy-benzyl, to virtues such as nitrobenzyls Fragrant race group.Particularly preferably it is susceptible to the tert-butyl group or the benzyl of racemization impact during deprotection.It addition, R³⁰Can also be and R³Phase Same implication.

R⁴⁰Or R⁵⁰Represent hydrogen or the blocking group PG of amino independently².As amino acid whose blocking group, including this Blocking groups whole known to skilled person.Such as, Greene watts can be enumerated and write " the protection group in organic synthesis Group (the 3rd edition) (Protective groups in organic synthesis) " (U.S., Wiley-Interscience is public Department) described in blocking group.Preferably enumerate benzyloxycarbonyl, acetyl group, trifluoroethyl carbonyloxy group, tert-butoxycarbonyl, fluorenes Ylmeth-oxycarbonyl, tri-chloroethoxy base carbonyl, trifluoroacetyl group, allyloxy carbonyl, benzyl, propargyl epoxide carbonyl, benzoyl Base, phthalyl, tosyl, nitrobenzenesulfonyl etc., but it is not limited to these examples.Wherein, preferably in the short time Can the benzyloxycarbonyl of deprotection, tert-butoxycarbonyl.R⁴⁰Or R⁵⁰Can respectively with R⁴And R⁵Implication identical.

In this specification, R¹⁵And R¹⁶When being integrally formed formation together with B (boron atom) as the ring of the blocking group of B, excellent Form slection becomes the saturated or group of undersaturated 3～10 rings that can be replaced.Here ring structure also includes volution, thick Ring.As can the looped group of shape, can enumerate pinacol, 2，2-dimethyl-1，3-propanediol, N methyldiethanol amine, 1,8- Diaminonaphthalene, N-methyliminodiacetic acid, 1,1,1-trihydroxy methyl ethane, catechol etc., but do not limit.Particularly preferably Pinacol.

In this specification, the alkyl of carbon number 1～7 is particularly preferably methyl, ethyl, n-pro-pyl, isopropyl, positive fourth Base, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl.The alkyl being optionally substituted by halogen refers in the alkyl of carbon number 1～7 arbitrarily The alkyl that the hydrogen atom of number is optionally substituted by halogen.It is preferably trifluoromethyl, but does not limit.The phenyl being replaced refer to phenyl or There is independently of one another the phenyl of substituent group in 1～3 position of phenyl.3～10 rings being replaced refer to 3～10 rings or Person has 3～10 rings of substituent group independently of one another in 1～3 position of 3～10 rings.The heterocyclic radical being replaced refers to miscellaneous Ring or there is independently of one another the heterocyclic radical of substituent group in 1～3 position of heterocycle.To such phenyl, 3～10 rings, Or the substituent group of heterocycle does not limit, it may include C_1-6Alkyl, C_1-6Alkoxyl, hydroxyl, amino or nitro etc..

The present invention's is new¹⁸In the manufacture method of F labelling BPA, such as, can illustrate following S operation, T operation, U operation, Or V operation, but it is not limited to this.Here, the blocking group used in following reaction equation can suitably change, however it is not limited to This example.

Operation S

Operation T

Operation U

Operation V

In the reaction of operation S～each operation of V, reaction temperature is different according to solvent, initiation material, reagent etc., can Properly select.It addition, the response time is different according to solvent, initiation material, reagent, reaction temperature etc., can properly select.

In the reaction of each operation, after reaction terminates, the target compound of each operation can be mixed from reaction according to conventional methods Compound is separated.

Target compound obtains the most as follows: (i) filters off the insoluble matters such as catalyst as required, and (ii) is to instead Mixture is answered to add water and solvent (such as, ethyl acetate, chloroform etc.) the extraction target compound not mixed, (iii) with water Washing organic layer, uses the such desiccant of anhydrous magnesium sulfate to be dried as required, and (iv) evaporates solvent.The target obtained Compound can utilize known method (such as, silica gel column chromatography etc.) to refine further as required.It addition, the mesh of each operation Mark compound also can not provide the next one to react refinedly.

(S operation)

That is, S-1 operation be make compound (401) in acidic aqueous solution with nitrite effect, generate diazol, manufacture Operation as the compound (402) of halogen derivatives.Compound (401) is known, commercially available but it also may by commercially available Compou nd synthesis and obtain.

As diazo-reaction reagent, the nitrous acid alkane such as sodium nitrite, potassium nitrite and isobutyl nitrite can be used Base ester etc..It addition, as iodination reagent, known sodium iodide, potassium iodide, iodine etc. can be enumerated.

The solvent used can enumerate water, acetone, acetonitrile, THF, methanol, ethanol etc. or mixing of more than two kinds in these Solvent, wherein, preferably shows inactive acetone to diazo-reaction.

Reaction temperature is preferably-20 DEG C～room temperature, more preferably-10 DEG C～5 DEG C.Response time is preferably 30 minutes～2 Hour, more preferably 30 minutes～1 hour.

(S-2 operation)

S-2 operation makes compound (402) react with halide reagent in the presence of a catalyst and manufacture compound (403) Operation.

The halide reagent used has N-bromosuccinimide, dibromo isocyanuric acid etc..Use the halogenation examination beyond bromo During agent, illustratively, 1,3-bis-iodo-5,5 '-dimethyl hydantoin, N-iodosuccinimide etc. can be enumerated.On the other hand, The catalyst used is the radical polymerization mixture such as peroxide, AIBN.

The solvent used is not particularly limited, and can enumerate benzene, chloroform, carbon tetrachloride, particularly preferably enumerate carbon tetrachloride.

Reaction temperature is preferably room temperature～120 DEG C, more preferably 70～100 DEG C.

Response time is preferably 1 hour～24 hours, more preferably 6 hours～18 hours.

S-3 is in the presence of base, makes compound (403) and is generally used for phase transfer catalyst and the modification that ball ridge is reacted Aminoacid reacts and the operation of coming of new compound (404).

As the modified amino acid in the ball ridge reaction used, do not limit, preferably enumerate N-diphenyl methylene glycine Methyl ester, N-diphenyl methylene glycine ethyl ester, N-diphenyl methylene glycine N-diphenyl methylene tert-butyl glycinate, 4-chlorine are sub- The benzyl glycine tert-butyl ester, N-diphenyl methylene glycine benzyl ester.Wherein, the particularly preferred N-tertiary fourth of diphenyl methylene glycine Ester.

The alkali used does not limits, and Lithium hydrate, sodium hydroxide, potassium hydroxide and triethylamine etc. are preferably used.From instead Speed is answered to consider, particularly preferred potassium hydroxide.

As the modified amino acid in the ball ridge reaction used, preferably enumerate O-pi-allyl-N-(9-anthracene methyl) gold bromide Chinine, (S)-(+) double (3,4,5-trifluorophenyl)-4,5-dihydro BR > the C-3H-dinaphtho of-4,4-dibutyl l-2,6-[7, 6,1,2-CDE] azepanBromide etc..

The preferred toluene of solvent of use, dichloromethane, chloroform etc..From the standpoint of environment, particularly preferred toluene.

Reaction temperature is preferably-20 DEG C～100 DEG C, more preferably-4 DEG C～room temperature.

Response time is preferably 30 minutes～24 hours, more preferably 1～18 hour.

The compound obtained can refine but it also may enter next operation the most refinedly.

(S-4 operation)

S-4 operation is the operation making compound (404) slough amido protecting body in acidic aqueous solution.Molten as use Agent, can enumerate citric acid or oxalic acid aqueous solution and acetone, acetonitrile, the mixed solvent of THF, DMF, DMSO, from the sight evaporating solvent Point considers, preferred example is citric acid or oxalic acid aqueous solution and acetone, acetonitrile or the mixed solvent of THF.

Here, reaction temperature is preferably room temperature～100 DEG C, more preferably room temperature～80 DEG C.Response time is preferably 30 points Clock～24 hours, more preferably 1～3 hour.

(S-5 operation)

S-5 operation is that compound (405) uses protection reagent protect the operation of amino in the basic conditions.Do not limit In the compound illustrated, the protection reagent of use can enumerate benzyl chloroformate, Bis(tert-butoxycarbonyl)oxide etc..

The preferred Lithium hydrate of alkali, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the triethylamines etc. used, do not have There is restriction.The particularly preferably sodium carbonate of mitigation, potassium carbonate.

The solvent preferred amphiphilic solvent used.Particularly, acetone, acetonitrile, THF, DMF, DMSO can be enumerated, molten from evaporating From the viewpoint of agent, preferably acetone, acetonitrile, THF.

Reaction temperature is preferably-20 DEG C～100 DEG C, more preferably-4 DEG C～room temperature.Response time be preferably 30 minutes～ 24 hours, more preferably 3 hours～18 hours.

(S-6 operation)

S-6 operation is the operation that compound is manufactured trialkyl tin compound by Suzuki-Pu, palace coupling reaction.As instead Answer reagent, use benzyl stannum, as catalyst, normally used palladium catalyst in Suzuki-Pu, palace coupling reaction can be enumerated, such as Cinnamyl palladium chloride complex, acid chloride, three (dibenzalacetone) two palladium, four (triphenyl phenyl phosphino-) palladium etc., but do not limit In these.Wherein, preferably four (triphenyl phenyl phosphino-) palladium.

Alkali used can use Lithium hydrate, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate And triethylamine etc., but the sodium acetate more preferably relaxed, potassium acetate.

Use the preferred toluene of solvent, twoAlkane etc..Reaction temperature is preferably room temperature～150 DEG C, more preferably 80 DEG C～ 120℃.Response time is preferably 1 hour～48 hours, more preferably 2 hours～24 hours.

(S-7 operation)

Additionally, the S-7 operation that compound (407) is made compound (408) does not limit, following operation can be illustrated.

Compound (407) is dissolved in solvent, under nitrogen flowing, adds the iodine such as Koser ' s reagent

Use solvent can enumerate water, dichloromethane, acetone, acetonitrile, THF, methanol, ethanol, trifluoroethanol etc. or this Mixed solvent of more than two kinds in Xie, wherein, preferably dichloromethane.

Reaction temperature is preferably-20 DEG C～room temperature, more preferably-10 DEG C～5 DEG C.Response time is preferably 30 minutes～2 Hour.

(S-8 operation)

As compound (408) being made the reagent used in the S-8 operation of compound (409), fluohydric acid gas can be enumerated.

Use solvent can enumerate water, dichloromethane, acetone, acetonitrile, THF, methanol, ethanol, DMF, DMSO etc. or this Mixed solvent of more than two kinds in Xie, wherein, preferably individually dichloromethane or acetonitrile, the combination of DMF, DMSO.

Reaction temperature is preferably-20 DEG C～180 DEG C, more preferably 80 DEG C～160 DEG C.Response time is preferably 5 minutes～2 Hour, more preferably 10 minutes～1 hour.

(S-9 operation)

S-9 operation is in the presence of palladium catalyst and part, compound 409 is used pinacol borating agent, and uses Microwave irradiations etc., manufacture the operation of pinacol boronic acid derivatives.As the catalyst used, Suzuki-Pu, palace coupling can be enumerated anti- Normally used palladium catalyst in Ying, such as cinnamyl palladium chloride complex, acid chloride, three (dibenzalacetone) two palladium etc., But it is not limited to these.

Microwave irradiation conditions is preferably room temperature～200 DEG C, more preferably 80 DEG C～180.Response time be preferably 1 minute～ 60 minutes, more preferably 5 minutes～30 minutes.

As ligand, normally used phosphorus system ligand, such as thricyclohexyl in Suzuki-Pu, palace coupling reaction can be enumerated Phosphine, 2-dicyclohexyl phosphino--2,4,6-tri isopropyl biphenyl, 2-dicyclohexyl phosphino--2 ,-(N, N)-dimethylamino biphenyl, 3,5-dimethoxy-2-dicyclohexyl phosphino--2,4,6-tri isopropyl biphenyl, 3,5-dimethoxy-2-di-t-butyl phosphino--2, 4,6-tri isopropyl biphenyls etc., but it is not limited to these.

Alkali used can use Lithium hydrate, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and triethylamine etc., But do not limit.The particularly preferably sodium carbonate of mitigation, potassium carbonate.

Use solvent be preferably toluene, twoAlkane, DMDO etc..

(T-1 operation)

T-1 operation is that compound 501 iodate is manufactured the operation of compound 502.In iodination reaction, perchloric acid can be enumerated The metal perchlorate such as sodium, sodium perchlorate and iodine or the method for sodium iodide such iodate metal reaction, and at sulphuric acid, fluoroform The method using the such iodination reagent of N-iodosuccinimide in the such strong acid of sulfonic acid.

(T-2 operation)

T-2 operation is that compound (502) uses in the basic conditions protection reagent to protect the operation of amino.Do not limit In the compound illustrated, the protection reagent of use can enumerate benzyl chloroformate, Bis(tert-butoxycarbonyl)oxide etc..

(T-3 operation)

T-3 operation is that compound (503) uses protection reagent to protect the operation of carboxyl.

Use solvent can enumerate acetone, ethyl acetate, chloroform, THF, twoAlkane, methanol, ethanol etc., preferably to reduction The inactive methanol of reaction and display, ethanol.

Reaction temperature is preferably-20 DEG C～100 DEG C, more preferably room temperature～50 DEG C.Response time be preferably 30 minutes～ 24 hours, more preferably 3～18 hours.

(T-4 operation)

T-4 operation is the nitro of compound 504 to be reduced into amino and manufactures the operation of compound 505.Can enumerate and make For inorganic salt such with calcium chloride or the such acid reaction of hydrochloric acid in the presence of the ferrum of reducing agent, zinc, stannum, additionally at palladium, rubidium, ruthenium Or in the presence of its coordination compound, use hydrogen reducing, but it is not limited to this.

The solvent used can enumerate acetone, acetonitrile, THF, methanol, ethanol etc., preferably shows reduction reaction inactive Methanol, ethanol.

(T-5 operation)

T-5 operation is via diazonium by compound (505)And manufacture the operation of halogen derivatives (506).As diazonium Change reaction reagent, use the alkyl nitrites etc. such as sodium nitrite, potassium nitrite and isobutyl nitrite.It addition, as iodine Change reagent, known sodium iodide, potassium iodide, iodine etc. can be enumerated.

Thus obtained halogen derivatives (506), with S-6～S-9 operation similarly by for compound 410 as Compou nd synthesis.

(U-1 operation～U-4 operation)

Additionally, operation U-1～U-4 are the operations as operation S-2～S-5, be prepare compound 601,602,603, The operation of 604 and 605.

(U-5 operation)

U-5 operation is to manufacture the operation of anil by compound (605) is carried out hydro-reduction.As use Catalyst, use palladium dydroxide, palladium carbon etc., but be not limited to this.

(U-6 operation)

U-6 operation is via diazonium by compound (606)And manufacture the operation of triazenes derivant (607).

As diazo-reaction reagent, use the nitrous acid alkyl such as sodium nitrite, potassium nitrite and isobutyl nitrite Ester etc..It addition, as reaction reagent, known dimethylamine, Aminocyclopentane, cyclohexylamine etc. can be enumerated.

Reaction temperature is preferably-20 DEG C～room temperature, more preferably-10 DEG C～5 DEG C.Response time is preferably 30 minutes～2 Hour, more preferably 30 minutes～1 hour.Compound (611) can also be manufactured by compound (607).

(U-7 operation)

U-7 operation is via diazonium by compound (606)And manufacture the operation of halogen derivatives (608).As diazonium Change reaction reagent, use the alkyl nitrites etc. such as sodium nitrite, potassium nitrite and isobutyl nitrite.It addition, as iodine Change reagent, known sodium iodide, potassium iodide, iodine etc. can be enumerated.

(U-8 operation)

U-8 operation is that by Suzuki-Pu, palace coupling reaction, compound (608) is manufactured trialkyl tin compound (609) Operation.As reaction reagent, tributyl tin, tin trimethyl etc. can be enumerated.It addition, as the catalyst used, bell can be enumerated Normally used palladium catalyst in wood-Pu, palace coupling reaction, such as cinnamyl palladium chloride complex, acid chloride, three (dibenzylidenes Acetone) two palladiums, four (triphenyl phenyl phosphino-) palladium etc., but it is not limited to these.Wherein, preferably four (triphenyl phenyl phosphino-) palladium.

(U-9 operation)

The U-9 operation that compound (609) makes compound (610) is not limited, the steps can be illustrated.

Compound (609) is dissolved in solvent, adds the iodine such as Koser ' s reagent under nitrogen flowing

(U-10 operation)

As Compound Compound (610) being made the reagent used in the U-10 operation of compound (611), fluorine can be enumerated Change hydrogen.

(U-11 operation)

U-11 operation is by the method as S-9 operation, by the presence of palladium catalyst and part, to compound 611 use pinacol borating agent, and use microwave irradiation, manufacture the operation of pinacol boronic acid derivatives.

(U-12 operation)

U-12 operation is in the presence of DMAP, and compound (608) uses Bocization reagent manufacture di-Boc acid derivative Operation.

Solvent used can use toluene, twoAlkane, acetone, DMF, DMSO, MeCN etc., but do not limit.Particularly preferably Acetone, MeCN.

Reaction temperature is preferably room temperature～100 DEG C, more preferably 30 DEG C～60 DEG C.

Response time is preferably 8 hours～48 hours, more preferably 12 hours～24 hours.

(U-13 operation)

U-13 operation is that by Suzuki-Pu, palace coupling reaction, compound (613) is manufactured trialkyl tin compound (614) Operation.As reaction reagent, tributyl tin, tin trimethyl etc. can be enumerated.It addition, as the catalyst used, bell can be enumerated Normally used palladium catalyst in wood-Pu, palace coupling reaction, such as cinnamyl palladium chloride complex, acid chloride, three (dibenzylidenes Acetone) two palladiums, four (triphenyl phenyl phosphino-) palladium etc., but it is not limited to these.Wherein, preferably four (triphenyl phenyl phosphino-) palladium.

Use solvent be preferably toluene, twoAlkane etc..Reaction temperature is preferably room temperature～150 DEG C, more preferably 80 DEG C ～120 DEG C.Response time is preferably 1 hour～48 hours, more preferably 2 hours～24 hours.

(U-14 operation)

U-14 operation is to be obtained Diaryl iodonium by tin compound (614)The operation of salt (615).This operation limits the most especially Fixed, the steps can be illustrated.

Under nitrogen flowing, the iodine such as Koser ' s reagent are added to tin compound (614)Manufacture.

Use solvent can enumerate water, dichloromethane, acetone, acetonitrile, THF, methanol, ethanol, 2,2,2 tfifluoroethyl alcohol, 1, 1,1,3,3,3-hexafluoroisopropanol etc. or mixed solvent of more than two kinds in these, wherein, preferably dichloromethane, 2,2,2-tri- Fluoroethanol, 1,1,1,3,3,3-hexafluoroisopropanol.

Reaction temperature is preferably-20 DEG C～60 DEG C, more preferably-10 DEG C～room temperature.Response time is preferably 30 minutes～2 Hour.

(U-15 operation)

U-15 operation is by Diaryl iodoniumSalt (615) obtains the operation of fluorinated compound (616).As in U-15 operation The reagent used, can enumerate fluohydric acid gas, potassium fluoride, cesium fluoride.

Use solvent can enumerate water, dichloromethane, acetone, acetonitrile, THF, methanol, ethanol, DMF, DMSO etc. or this Mixed solvent of more than two kinds in Xie, wherein, preferably individually dichloromethane, single acetonitrile, single DMF, individually DMSO or combinations thereof.

(U-16 operation)

U-16 operation is in the presence of palladium catalyst and part, compound (616) is used pinacol borating agent, and adopts With microwave irradiation, manufacture the operation of pinacol boronic acid derivatives.

As the catalyst used, normally used palladium catalyst, such as Cortex Cinnamomi in Suzuki-Pu, palace coupling reaction can be enumerated Base palladium chloride complex, acid chloride, three (dibenzalacetone) two palladium etc., but it is not limited to these.

Use solvent be preferably toluene, twoAlkane, DMDO etc..

(U-17 operation)

U-17 operation is by salt exchange reaction, compound (615) to be replaced counter anion and obtain compound (618) Reaction.As reaction reagent, sodium chloride, potassium bromide etc. can be enumerated.

(U-18 operation)

As the reagent used in U-18 operation, fluohydric acid gas, potassium fluoride, cesium fluoride can be enumerated.

(U-19 operation)

U-19 operation is in the presence of palladium catalyst and part, and compound (608) is used pinacol borating agent, manufactures The operation of pinacol boronic acid derivatives.As the catalyst used, normally used palladium in Suzuki-Pu, palace coupling reaction can be enumerated Catalyst, such as, dichloro double (triphenylphosphine) palladium, cinnamyl palladium chloride complex, acid chloride, three (dibenzalacetone) two palladium Deng, but it is not limited to these.

Alkali used can use sodium acetate, potassium acetate, Lithium hydrate, sodium carbonate, potassium carbonate and triethylamine etc., but does not has There is restriction.The particularly preferably sodium acetate of mitigation, potassium acetate.

Use solvent be preferably toluene, twoAlkane, DMSO etc..Reaction temperature is preferably room temperature～150 DEG C, more preferably 80 DEG C～120.

Response time is preferably 30 minutes～48 hours, more preferably 2 hours～18 hours.

(U-20 operation)

U-20 operation is in the presence of copper catalyst, makes compound (619) react with fluorination reagent and obtain compound (616) operation.As the fluorination reagent used, fluohydric acid gas, potassium fluoride can be enumerated.

Use solvent can enumerate toluene, twoAlkane, DMF, DMSO, MeCN etc., more preferably DMF, MeCN.

Reaction temperature is room temperature～150 DEG C, more preferably 80 DEG C～120 DEG C.

Response time is preferably 1 minute～60 minutes, more preferably 5 minutes～30 minutes.

(V-1 operation～V-4 operation)

V-1～V-4 operation be with the operation as operation S-2～S-5 to prepare compound 701,702,703,704 and The operation of 705.

(V-5 operation)

Additionally, V-5 operation is as U-11 operation.

In each derivant, time in compound containing F, Ke Yiyong¹⁸F replaces F to be marked.

Such as, to H₂ ¹⁸O irradiates the proton accelerated, and passes through¹⁸(p n) is synthesized H to O¹⁸F-Fluohydric acid. so that it is pass through ion Exchange resin column and adsorb, with the H of the raw material as non-adsorbed₂ ¹⁸O separates.Use K₂CO₃Aqueous solution carries out eluting to this post and obtains To K⁺¹⁸F^-, nucleopilic reagent can be used it for.

In the compound of the present invention, before Fization, there is N=N-NR₇R₈Time, utilize known method to realize¹⁸F labelling.That is, will Obtain¹⁸F anion is as nucleopilic reagent, in organic solvent, heats and obtain label together with phase transfer catalyst.

Additionally, be Sn (R₆)₃Time, the method for available Ermert et al. obtains (non-patent literature J.Label.Compd.Radiopharm.,47,429,2004.).That is, with hydroxyls (tosyl oxo) such as Koser ' s reagent Iodo aromatic hydrocarbon is reacted, and temporarily makes diallyl iodineSalt, makes nucleopilic reagent¹⁸F^-React, the most efficiently obtain label.

Additionally, each blocking group can utilize conventional method to carry out deprotection, make target Fization BPA.

The method of the application of the invention, such¹⁸The yield of F labelled compound is preferable, and can be with better than degree State obtains.

Embodiment

By below example, the present invention is described in more detail, but the present invention is not limited to this.

Should illustrate, in following embodiment, the analysis of compound and separation and purification use following instrument kind, reagent Carry out.

H NMR spectroscopy: NEC company system, JNM-AL series A L400 400MHz

Microwave irradiation: Biotage company system, Initiator+

UPLC analyzes: Waters company of Japan system, ACQUITY UPLC system

(embodiment 1)

The manufacture of 4-bromo-2-iodotoluene

Make 4-bromo-2-amino toluene (10.0g, 53.7mmol) be suspended in 30% sulphuric acid (100mL), ice-cold under, from drip Liquid funnel is slowly added dropwise the aqueous solution (15mL) of sodium nitrite (3.89g, 56.4mmol) wherein.Stir 45 minutes at 0 DEG C, its After make sodium iodide (12.1g, 80.6mmol) be dissolved in water (50mL), in this aqueous solution, add above-mentioned diazonium salt solution.In room Lower stirring 1 hour further of temperature, after being extracted with ethyl acetate 3 times, cleans ethyl acetate layer 1 time with saturated aqueous common salt, uses sulfur Acid magnesium is dried, and concentrating under reduced pressure.Thereafter, utilize silicagel column (normal hexane) to refine, obtain object (9.0g, 45%).

¹H-NMR(CDCl₃)；2.37(s,3H,CH₃), 7.08 (d, J=8.0,1H, Ar), 7.35 (dd, J=1.6,8.0, 1H, Ar), 7.93 (d, J=2.0,1H, Ar).

The manufacture of 4-bromo-2-iodine bromobenzyl

By the 4-bromo-2-iodotoluene (9.00g, 23.9mmol) obtained in last operation, N-bromosuccinimide (5.95g, 33.5mmol) and 2,2-azo double (2-methyl propionitrile) (39mg, 2.4mmol) joins carbon tetrachloride (100mL), The lower reaction of backflow 18 hours.Thereafter, filtering reacting liquid, filtrate is carried out concentrating under reduced pressure.Then, utilize silica gel column chromatography (just own Alkane) refine, obtain object 7.0g (78%).

¹H-NMR(CDCl₃)；4.53(s,2H,CH₂), 7.32 (d, J=8.0,1H, Ar), 7.46 (dd, J=2.0,8.4, 1H, Ar), 7.93 (d, J=2.0,1H, Ar).

The manufacture of 3-(4-bromo-2-iodophenyl)-2-(diphenyl methylene amino) benzyl propionate

Cesium hydrate. (7.54g, 50.3mmol), N-(diphenyl methylene) glycine benzyl ester is added in toluene (100mL) (5.50g, 16.7mmol) and O-pi-allyl-N-9-anthracene methyl bromide quinine (1.10g, 1.67mmol, 0.1 equivalent).Cold But to after 0 DEG C, while this toluene mixed solution is stirred vigorously limit disposably add the compound obtained in last operation Toluene (10mL) solution of (6.30g, 16.7mmol).After completion of dropwise addition, this state is kept to stir 18 hours.Thereafter, ether is used (50mL) reaction solution is extracted 2 times, after this ether layer being carried out with saturated aqueous common salt further, be dried with magnesium sulfate, and Concentrating under reduced pressure, obtains thick object (8.7g).Should illustrate, not refine and be directly entered next operation.

The manufacture of 2-amino-3-(4-bromo-2-iodophenyl) benzyl propionate

Make compound 3-(4-bromo-2-iodophenyl)-2-(diphenyl methylene amino) benzyl propionate obtained in last operation (8.6g) it is dissolved in THF (86mL), is added thereto to 30% aqueous citric acid solution (50mL) further.This mixed solution is made to occur 1 hour back flow reaction.After reaction terminates, after cleaning with ether (80mL), neutralize with potassium carbonate.Thereafter, extract with EtOAc (80mL) 2 times, dried with magnesium sulfate, and concentrating under reduced pressure.Carry out further with silica gel column chromatography (ethyl acetate/normal hexane=1/1) Refined, obtain object (2.40g, yield 31%).

¹H-NMR(CDCl₃)；2.90 (dd, J=8.4,13.6,1H, CH₂-α), 3.18 (dd, J=6.4,13.6,1H, CH₂-β), 3.83 (dd, J=6.4,8.2,1H, CH), 5.14 (m, 2H, CH₂Ar), 7.01 (d, J=8.4,1H, Ar), 7.26- 7.39 (m, J=6.0,8.4,1H, Ar), 7.96 (d, J=2.4,1H, Ar).

The manufacture of 3-(2-bromo-4-iodophenyl)-2-(Benzyoxycarbonylamino) benzyl propionate

Above-claimed cpd 2-amino-3-(4-bromo-2-iodophenyl) benzyl propionate (2.32g, 5.44mmol) is dissolved in THF (50mL), it is added thereto to H₂O (50mL) and K₂CO₃(903mg, 6.53mmol), ice-cold lower stirring.It is slowly added into wherein Solution obtained by being added in acetonitrile (10mL) by benzyl chloroformate (1.11g, 6.53mmol), stirs 12 hours under room temperature.Use second Reaction solution is extracted 3 times by acetoacetic ester (50mL), with 10% aqueous citric acid solution (50mL) to organic layer cleaning 3 times, further Clean 2 times with saturated aqueous common salt (50mL), use MgSO₄It is dried.After organic layer is concentrated, with flash column chromatography (hexane: acetic acid second Ester=6:1) refine, thus obtain the object (2.68g, 83%) as colorless oil.

¹H-NMR(CDCl₃)；3.10 (dd, J=8.0,14.8,1H, CH₂-α), 3.26 (dd, J=6.4,14.8,1H, CH₂-β),4.73(m,1H,CH),5.06(m,2H,CH₂Ar),5.15(s,2H,CH₂Ar), 5.30 (m, J=8.0,1H, NH), 7.24-7.36 (m, 11H, Ar), 7.91 (d, J=1.7,1H, Ar).

The manufacture of 2-(Benzyoxycarbonylamino)-3-(the bromo-2-of 4-(three normal-butyl stannyls) phenyl) benzyl propionate

By PdCl under Ar environment₂(dppf) (40mg, 0.049mmol), double (pinacol conjunction) two boron (274mg, 1.08mmol) it is dissolved in DMSO (5mL) with potassium acetate, is stirred at room temperature.It is added thereto to above-claimed cpd 3-(the bromo-4-of 2- Iodophenyl)-2-(Benzyoxycarbonylamino) benzyl propionate (515mg, 0.979mmol) DMSO solution (2mL) after, stir at 80 DEG C Mix 24 hours.With ethyl acetate (70mL) diluting reaction solution, after carrying out kieselguhr filtration, clean with water and saline solution, use MgSO₄It is dried organic layer.Organic layer is filtered, after being concentrated by organic solvent, utilizes column chromatography (hexane: ethyl acetate=9:1) Refine, thus obtain the object as colorless oil.(381mg, 74%)

¹H-NMR(CDCl₃)；0.85 (t, J=7.6,9H ,-CH₂CH₂ CH ₃×3),1.05(m,6H,-CH ₂CH₂CH₃×3), 1.27-1.45(m,6H,-CH₂ CH ₂CH₃× 3), 3.01 (dd, J=9.2,14.4,1H, CH₂-α), 3.48 (dd, J=4.4, 14.4,1H,CH₂-β),4.53(m,1H,CH),5.04(s,2H,CH₂Ar),5.20(m,2H,CH₂Ar), 6.95 (d, J=7.6, 1H,Ar),7.10-7.44(m,12H,Ar).

(2-(3 benzyloxy-2-(Benzyoxycarbonylamino)-3-oxygen propyl group)-5-bromophenyl) (3-methoxyphenyl) iodine The manufacture of toluene fulfonate

To above-claimed cpd 2-(Benzyoxycarbonylamino)-3-(the bromo-2-of 4-(three normal-butyl stannyls) phenyl) propanoic acid Benzyl ester (154mg, 0.228mmol) adds trifluoroethanol (2mL), and nitrogen flows down, and stirs 1 hour in ice-water bath.Under ice-cold, add Enter iodineSalt (96.10mg, 0.228mmol), stirs 15 minutes in ice-water bath.At room temperature solvent in reaction mixture is evaporated Go, add hexane (10mL) to the mixture obtained and be carried out, remove solvent portions by decant.Carry out 2 same behaviour Make, evaporate the residual solvent of the mixture obtained the most completely, obtain object (159mg, 80%).

¹H-NMR(DMSO-d₆)；2.29(s,3H,TsOH-CH₃), 3.23 (dd, J=10.8,14.8,1H, CH₂-α), 3.39(m,1H,CH₂-β,overlapped with water),3.75(s,3H,-OCH₃),4.51(m,1H,CH),5.00(m, 2H,BnCH₂),5.17(s,2H,BnCH₂), 7.12 (d, J=8.0,2H, TsOH-Ar), 7.19-8.06 (m, 19H, Ar).

The manufacture of 2-(Benzyoxycarbonylamino)-3-(4-bromo-2-fluorophenyl) benzyl propionate

By above-claimed cpd (2-(3 benzyloxy-2-(Benzyoxycarbonylamino)-3-oxygen propyl group)-5-bromophenyl) (3-methoxy Base phenyl) iodineToluene fulfonate (100mg, 0.115mmol) and kryptofix 2.2.2 (43.1mg, 0.115mmol) and fluorine Change potassium (6.7mg, 0.115mmol), in DMF (10mL), is stirred 15 minutes at 100 DEG C.After reaction terminates, decompression evaporates solvent, With silica gel column chromatography (hexane: ethyl acetate=7:1), the residue obtained is refined, obtain target compound (34.0mg, 61%).

¹H-NMR(CDCl₃)；3.05 (dd, J=6.4,14.0,1H, CH₂-α), 3.16 (dd, J=5.6,14.0,1H, CH₂-β),4.67(m,1H,CH),5.08(m,2H,BnCH₂),5.13(s,2H,BnCH₂), 5.31 (d, J=8.0,1H, NH), 6.86(m,1H,Ar),7.09-7.15(m,2H,Ar),7.26-7.37(m,10H,Ar).

2-(Benzyoxycarbonylamino)-3-(the fluoro-4-of 2-(4,4,5,5-tetramethyl 1,3,2 dioxy boron penta ring-2-base) benzene Base) manufacture of-benzyl propionate

Nitrogen flows down, and makes PdCl₂(dba) (27.5mg, 0.03eq.) and three ring phosphines (tricyclophosphine) (16.8mg, 0.06eq.) is suspended in twoAlkane (5mL), after stirring 30 minutes, double (pinacol conjunction) two boron of interpolation (305mg, 1.20mmol) with potassium acetate (294mg, 3.00mmol), add above-claimed cpd 2-(Benzyoxycarbonylamino)-3-further (4-bromo-2-fluorophenyl) benzyl propionate (486mg, 1.00mmol).

Thereafter, 150 DEG C of microwave irradiations 15 minutes, object (421mg, 79%) is thus obtained.

¹H-NMR(CDCl₃)；3.14 (dd, J=8.8,13.6,1H, CH₂-α), 3.20 (dd, J=5.2,13.6,1H, CH₂-β),4.69(m,1H,CH),5.08(m,1H,BnCH₂),5.14(s,1H,BnCH₂), 5.30 (d, J=8.0, NH), 7.05 (t, J=7.3,1H, Ar), 7.26-7.50 (m, 12H, Ar).

(embodiment 2)

The manufacture of 2-(tertbutyloxycarbonylamino)-3-(2-iodo-4-nitrobenzophenone) propanoic acid tert-butyl ester

Make 4-nitrophenylalanine (1.00g, 4.76mmol) be dissolved in trifluoromethanesulfonic acid (5mL), through 15 minutes points 3 times to Wherein add N-iodosuccinimide (963mg, 0.9eq.).The most at room temperature reaction 18 hours.

Thereafter, in frozen water, above-mentioned reactant liquor is added, further with potassium carbonate by pH regulator to more than 12.Further Add Boc₂The acetonitrile solution (about 10mL) of O (1.25g, 5.71mmol), at room temperature, stirs 18 hours.After reaction terminates, use Citric acid, by pH regulator to less than 4, extracts 3 times by ethyl acetate (50mL), further with water (100mL), saturated aqueous common salt (100mL) this organic layer is carried out.Dried with magnesium sulfate, carry out concentrating under reduced pressure, thus obtain middle crude product.Enter one The step tert-butyl alcohol (20mL) dissolves this crude product 503, adds Boc₂After O (1.25g, 5.71mmol), interpolation DMAP (116mg, 0.951mmol).Thereafter, 18 hours it are stirred at room temperature.After reaction terminates, after decompression evaporates solvent, carry out with silica gel column chromatography Refined, obtain object 2-(tertbutyloxycarbonylamino)-3-(2-iodo-4-nitrobenzophenone) propanoic acid tert-butyl ester (1.26g, 54%).

¹H-NMR(CDCl₃)；1.35(s,12H,pinacol-CH₃× 4), 1.42 (s, 9H, t-Bu), 3.10 (dd, J= 8.4,13.6,1H,CH₂-α), 3.18 (dd, J=6.4,13.6,1H, CH₂-β), 3.83 (dd, J=6.4,8.2,1H, CH), 5.14(m,2H,CH₂Ar), 7.41 (d, J=8.4,1H, Ar), 8.13 (dd, J=2.0,8.4,1H, Ar), 8.68 (d, J= 2.0,1H,Ar).

The manufacture of 2-(tertbutyloxycarbonylamino)-3-(4-amino-2-iodophenyl) propanoic acid tert-butyl ester

Make above-claimed cpd 2-(tertbutyloxycarbonylamino)-3-(2-iodo-4-nitrobenzophenone) propanoic acid tert-butyl ester (2.32g, 4.71mmol) it is dissolved in ethanol (23mL), after adding iron powder (0.657g, 2.5eq.) further, is warming up to 80 DEG C.Thereafter, one Secondary property is added ammonium chloride (0.252g, 1.0eq.) and is dissolved in aqueous solution obtained by water (2mL).React 1 hour at 80 DEG C further.Instead After should terminating, after filtering iron powder etc., filtrate is carried out concentrating under reduced pressure.Dissolve concentrate by ethyl acetate (50mL), use water (50mL) clean with saturated aqueous common salt (50mL), dried with magnesium sulfate, after filtration, filtrate is carried out concentrating under reduced pressure.Utilize silicon This residue is refined by glue column chromatography (ethyl acetate/normal hexane=1/2), obtains target compound (1.00g, 46%).

¹H-NMR(CDCl₃)；1.39(s,12H,pinacol-CH₃× 4), 1.42 (s, 9H, t-Bu), 2.92 (dd, J= 7.2,14.0,1H,CH₂-α), 3.11 (dd, J=5.6,14.0,1H, CH₂-β), 4.45 (m, 1H, CH), 4.99 (m, J=8.4, 1H, NH), 6.59 (dd, J=2.4,8.4,1H, Ar), 6.95 (d, J=8.4,1H, Ar), 7.18 (d, J=2.4,1H, Ar).

The manufacture of 2-(tertbutyloxycarbonylamino)-3-(4-bromo-2-iodophenyl) propanoic acid tert-butyl ester

By above-claimed cpd 2-(tertbutyloxycarbonylamino)-3-(4-amino-2-iodophenyl) propanoic acid tert-butyl ester (2.5g, 5.41mmol) for conventional sandmeyer reaction, obtain brominated compound 2-(the tertbutyloxycarbonylamino)-3-of target (4-bromo-2-iodophenyl) propanoic acid tert-butyl ester (1.56g, 55%).

¹H-NMR(CDCl₃)；1.37(s,12H,pinacol-CH₃× 4), 1.43 (s, 9H, t-Bu), 2.98 (dd, J= 8.4,13.6,1H,CH₂-α), 3.20 (dd, J=5.6,14.0,1H, CH₂-β), 4.51 (m, 1H, CH), 5.04 (d, J=9.2, 1H, NH), 7.10 (d, J=8.0,1H, NH), 7.39 (dd, J=1.6,8.0,1H, Ar), 7.97 (d, J=1.6,1H, Ar).

In addition it is possible to use compound 2-(tertbutyloxycarbonylamino)-3-(4-bromo-2-iodophenyl) propanoic acid tert-butyl ester, Make pinacol boronated compound similarly to Example 1.

(embodiment 3)

The manufacture of 4-bromo-2-nitro bromobenzyl

Utilize the method as the bromination of above-described embodiment 1, obtain target compound 4-bromo-2-nitro bromobenzyl.

¹H-NMR(CDCl₃)；4.78(s,2H,CH₂), 7.46 (d, J=8.0,1H, Ar), 7.74 (m, J=2.0,8.1, 1H, Ar), 8.18 (d, J=1.7,1H, Ar).

The manufacture of 2-amino-3-(4-bromo-2-nitrobenzophenone) propanoic acid tert-butyl ester

Utilize with 3-(4-bromo-2-iodophenyl)-2-(diphenyl methylene amino) benzyl propionate of embodiment 1 and 2-amino- 3-(4-bromo-2-iodophenyl) benzyl propionate manufacture same method, obtain target compound.

¹H-NMR(CDCl₃)；1.45 (s, 9H, t-Bu), 3.08 (dd, J=8.8,13.6,1H, CH₂-α),3.29(dd,J =5.6,13.6,1H, CH₂-β), 3.62 (dd, J=5.6,8.5,1H, CH), 7.31 (d, J=8.4,1H, Ar), 7.66 (dd, J =2.0,8.4,1H, Ar), 8.10 (d, J=2.0,1H, Ar).

The manufacture of 3-(4-bromo-2-nitrobenzophenone)-2-(tertbutyloxycarbonylamino) propanoic acid tert-butyl ester

Using the compound that obtains in N-(diphenyl methylene) tert-butyl glycinate and last operation as initial substance, pass through Amido protecting reaction similarly to Example 1, obtains target compound.

¹H-NMR(CDCl₃)；1.75 (s, 12H), 1.44 (s, 9H, t-Bu), 3.08 (dd, J=8.0,13.2,1H, CH₂- α), 3.29 (dd, J=5.2,13.5,1H, CH₂-β), 4.54 (m, 1H, CH), 5.15 (d, J=8.0,1H, NH), 7.29 (d, J =8.4,1H, Ar), 7.65 (dd, J=1.7,8.0,1H, Ar), 8.11 (d, J=1.7,1H, Ar).

The manufacture of 3-(2-amino-4-bromophenyl)-2-(tertbutyloxycarbonylamino) propanoic acid tert-butyl ester

Make the compound (1.0g.2.25mmol) obtained in last operation be dissolved in ethanol (10mL), add ferrum further After powder (0.314g, 2.5eq.), it is warming up to 80 DEG C.Thereafter, disposably add ammonium chloride (0.120g, 1.0eq.) and be dissolved in water (2mL) aqueous solution obtained by.React 1 hour at 80 DEG C further.After reaction terminates, after iron powder etc. is filtered, filtrate is carried out Concentrating under reduced pressure.Dissolve concentrate by ethyl acetate (50mL), and be carried out with water (50mL) and saturated aqueous common salt (50mL), use Magnesium sulfate is dried, after filtration, filtrate is carried out concentrating under reduced pressure.Utilize silica gel column chromatography (ethyl acetate/normal hexane=1/2) right This residue refines, and thus obtains target compound 606 (0.457g, 49%).

¹H-NMR(CDCl₃)；1.34(s,12H,pinacol-CH₃× 4), 1.44 (s, 9H, t-Bu), 2.77 (dd, J= 8.8,14.0,1H,CH₂-α), 3.14 (dd, J=3.6,13.6,1H, CH₂-β), 4.59 (m, 1H, CH), 5.41 (d, J=8.0, 1H, NH), 6.56 (d, J=1.7,1H, Ar), 6.86 (d, J=8.0,1H, Ar), 7.03 (dd, J=1.6,8.0,1H, Ar).

3-(the bromo-2-of 4-(pyrrolidin-1-yl-diazenyl) phenyl)-2-(tertbutyloxycarbonylamino) propanoic acid tert-butyl ester Manufacture

Dissolve the compound (60.0mg, 0.144mmol) obtained in last operation with MeCN (2mL), add water further (5mL).Thereafter, it is cooled to 0 DEG C, adds 12N HCl (1.2mL) further.Under the state maintaining 0 DEG C, dropping is dissolved in water (1mL) sodium nitrite (10.5mg, 0.152mmol).After completion of dropwise addition, 0 DEG C of further stirring 30 minutes.

It addition, when maintain 0 DEG C, in advance with MeCN (5mL), water (10mL) dissolve pyrrolidine (12.8mg, 0.181mmol) and potassium carbonate (100mg, 0.722mmol) obtained by mixed solution and dripping above-mentioned diazol hydrochlorate.Further After 0 DEG C of stirring 30 minutes, extract 2 times with chloroform (20mL), with water (15mL) saturated aqueous common salt (15mL), chloroform layer is carried out After cleaning, it is dried with magnesium sulfate.After filtration, carry out concentrating under reduced pressure, with silica gel column chromatography, the residue obtained is refined, obtain Target compound (32.3mg, 45%).

¹H-NMR(CDCl₃)；1.37(s,12H,pinacol-CH₃×4),1.39(s,9H,t-Bu),2.05(brs,4H, pyrrolidines-CH₂CH₂-), 3.06 (dd, J=9.2,13.2,1H, CH₂-α), 3.16 (dd, J=4.0,13.2,1H, CH₂-β),3.76(brs,2H,pyrrolidines-NCH₂-),3.97(brs,2H,pyrrolidines-NCH₂-),4.31(m, 1H, CH), 6.47 (d, J=6.4,1H, NH), 7.04 (d, J=8.0,1H, Ar), 7.16 (dd, J=2.0,8.0,1H, Ar), 7.56 (d, J=2.0,1H, Ar).

The manufacture of 3-(4-bromo-2-iodophenyl)-2-(tertbutyloxycarbonylamino) propanoic acid tert-butyl ester

Utilize the operation as the reaction using N-iodosuccinimide of embodiment 1, by 3-(2-amino-4-bromine Phenyl)-2-(tertbutyloxycarbonylamino) propanoic acid tert-butyl ester obtains target compound.

The manufacture of 3-(4-bromo-2-fluorophenyl)-2-(tertbutyloxycarbonylamino) propanoic acid tert-butyl ester

Utilize the method as S-6～S-8 operation, obtain target compound.

¹H-NMR(CDCl₃)；1.41(s,21H,pinacol-CH₃× 4, t-Bu), 2.98 (dd, J=6.8,14.0,1H, CH₂-α), 3.10 (dd, J=6.4,14.0,1H, CH₂-β), 4.43 (m, 1H, CH), 5.08 (d, J=7.6,1H, NH), 7.09 (t, J=8.0,1H, Ar), 7.20 (d, J=8.4,1H, Ar), 7.21 (d, J=8.4,1H, Ar).

2-(tertbutyloxycarbonylamino)-3-(the fluoro-4-of 2-(4,4,5,5-tetramethyl 1,3,2 dioxy boron penta ring-2-base) benzene Base) manufacture of-propanoic acid tert-butyl ester

Nitrogen flows down, and makes PdCl₂(dba) (27.5mg, 0.03eq.) and three ring phosphines (16.8mg, 0.06eq.) are suspended in twoAlkane (5mL), after stirring 30 minutes, add double (pinacol conjunction) two boron (305mg, 1.20mmol) and potassium acetate (294mg, 3.00mmol), above-claimed cpd 611 (418mg, 1.00mmol) is added further.Thereafter, 150 DEG C of microwave irradiations 15 minutes, Thus obtain object (372mg, 80%).

¹H-NMR(CDCl₃)；1.33(s,9H,-Boc),1.40(s,21H,t-Bu,pinacol(CH₃)₄),3.06(dd,J =8.8,13.6,1H, CH₂-α), 3.16 (dd, J=5.2,13.6,1H, CH₂-β), 4.45 (m, 1H, CH), 5.04 (d, J= 8.0,1H, NH), 7.20 (m, J=6.7,7.6,1H, Ar), 7.42-7.50 (m, 2H, Ar).

The manufacture of (embodiment 4) 2-(double (tert-butoxycarbonyl) amino)-3-(4-bromo-2-iodophenyl) propanoic acid tert-butyl ester

Make compound 3-(4-bromo-2-iodophenyl)-2-(tertbutyloxycarbonylamino) propanoic acid tert-butyl ester (1.50g, 2.6mmol) it is dissolved in MeCN (15mL), is added thereto to Boc₂O (1.16g, 5.33mmol), adds DMAP further (488mg,4.00mmol).It is heated up to 50 DEG C, at such a temperature reaction 24 hours.Thereafter, after solvent is carried out concentrating under reduced pressure, profit Refine with silica gel column chromatography (hexane: ethyl acetate=9:1), thus obtain the object as colorless oil (1.50g, 90%).

¹H-NMR(CDCl₃)；1.34-1.41 (m, 27H, t-Bu), 3.35 (dd, J=11.2,13.6,1H, CH₂-α), 3.46 (dd, J=4.4,14.0,1H, CH₂-β), 5.08 (dd, J=4.0,11.2,1H, CH), 7.00 (d, J=8.0,1H, Ar), 7.36 (dd, J=2.0,8.0,1H, Ar), 7.94 (d, J=2.0,1H, Ar).

2-(double (tert-butoxycarbonyl) amino)-3-(4-bromo-2-(tributylestannyl) phenyl) propanoic acid tert-butyl ester Manufacture

Make the compound (876.8mg, 1.40mmol) obtained in last operation be dissolved in toluene (4mL), be added thereto to Tetrakis triphenylphosphine palladium (80.88mg, 0.07mmol), adds double (tin trimethyl) (481.6mg, 1.47mmol) further.Add Temperature, to 120 DEG C, is reacted 3 hours at such a temperature.Thereafter, after solvent is carried out concentrating under reduced pressure, utilize silica gel column chromatography (hexane: Ethyl acetate=100:0～95:5) refine, thus obtain object as colorless oil (803.3mg, 86.5%).

¹H-NMR(CDCl₃)；0.36(s,9H,SnCH₃×3),1.39(s,18H,-Boc),1.48(s,9H,t-Bu), 3.28 (d, J=7.6,2H, CH₂), 4.84 (t, J=7.6,1H, CH), 6.95 (d, J=8.4,1H, Ar), 7.33 (dd, J= 2.0,8.4,1H, Ar), 7.48 (d, J=2.0,1H, Ar).

(2-(3-tert-butoxy-2-(Benzyoxycarbonylamino)-3-oxygen propyl group)-5-bromophenyl) (4-aminomethyl phenyl) iodine The manufacture of toluene fulfonate

The compound (663mg, 1.00mmol) obtained in last operation is made to be dissolved in 2,2,2-trifluoroethanols (40mL), to Wherein add 4-(hydroxyl (tosyl oxo) iodine) toluene (406mg, 1.00mmol), at room temperature reaction 15 minutes.With two Ether extracts, and is dried diethyl ether layer with magnesium sulfate.After filtration, carry out concentrating under reduced pressure, utilize silica gel column chromatography (hexane: acetic acid Ethyl ester=100:1～10:1) residue obtained is refined, obtain target compound (180mg, 20%).

¹H-NMR(CDCl₃)；1.35-1.47(m,27H,t-Bu),2.32(s,3H,TsO-CH₃),2.37(s,3H,Ar- CH₃), 3.38 (dd, J=8.0,14.4,1H, CH₂-α), 3.59 (dd, J=7.2,14.4,1H, CH₂-β), 5.05 (t, J= 7.6,1H, CH), 7.06 (d, J=8.0,2H, TsO-Ar), 7.18 (d, J=8.4,2H, Ar), 7.28 (d, J=8.4,1H, Ar), 7.53 (dd, J=1.6,8.4,1H, Ar), 7.61 (d, J=8.0,2H, TsO-Ar), 7.87 (d, J=1.6,1H, Ar), 7.91 (d, J=8.4,2H, Ar).

The manufacture of 2-(double (tert-butoxycarbonyl) amino)-3-(2-fluoro-4-bromophenyl) propanoic acid tert-butyl ester

Make 4,7,13,16,21,24-six oxygen-1,10-diazabicyclo [8.8.8] hexacosane (14.24mg, 0.04mmol) it is dissolved in MeCN (4mL), adds potassium fluoride (2.2mg, 0.04mmol) at 60 DEG C of concentrating under reduced pressure.Same operation After being repeated 3 times, it is dried 12 hours with vacuum pump pressure.2,2,6,6-tetramethyl piperidine 1-oxygen is added freely to the mixture obtained Base (1mg), adds the DMF solution (1mL) of compound 615 (28.0mg, 0.03mmol) further.It is heated up to 140 DEG C, in this temperature The lower reaction of degree 15 minutes.It is extracted with ethyl acetate, and with after saturated aqueous common salt cleaning ethyl acetate layer, is dried with sodium sulfate.Cross After filter, carry out concentrating under reduced pressure, obtain the mixture containing target compound.

UPLC analysis condition；Post: BEH C18 post (130A 1.7 μm 2.1mm × 150mm), flow velocity: 0.4mL/min, inspection Survey: 254nm, eluting solvent: 0.1% acetic acid aqueous solution: acetonitrile=30:70, detect time: 3.8min.

(2-(3-tert-butoxy-2-(Benzyoxycarbonylamino)-3-oxygen propyl group)-5-bromophenyl) (4-aminomethyl phenyl) bromination IodineManufacture

Make compound (2-(3-tert-butoxy-2-(Benzyoxycarbonylamino)-3-oxygen propyl group)-5-bromophenyl) (4-methyl Phenyl) iodineToluene fulfonate (58.9mg, 0.07mmol) is dissolved in ethyl acetate-water mixed liquid (1:1,2mL), adds wherein Enter potassium bromide (39.4mg, 0.33mmol), at room temperature reaction 5 hours.It is extracted with ethyl acetate, is dried acetic acid second with sodium sulfate Ester layer.After filtration, carry out concentrating under reduced pressure, obtain target compound (52.3mg, 99%).

¹H-NMR(CDCl₃)；1.38-1.54(m,27H,t-Bu),2.37(s,3H,Ar-CH₃), 3.40 (dd, J=8.4, 14.4,1H,CH₂-α), 3.61 (dd, J=7.2,14.4,1H, CH₂-β), 5.06 (t, J=7.6,1H, CH), 7.19 (d, J= 8.0,2H, Ar), 7.26 (d, J=8.0,1H, Ar), 7.52 (dd, J=1.6,8.0,1H, Ar), 7.85 (d, J=1.6,1H, Ar), 7.95 (d, J=8.4,2H, Ar).

2-(double (tert-butoxycarbonyl) amino)-3-(the bromo-2-of 4-(4,4,5,5-tetramethyl-1,3,2-dioxy boron penta ring- 2-yl) phenyl) manufacture of propanoic acid tert-butyl ester

PdCl is made under Ar environment₂(dppf) (98mg, 0.120mmol), double (pinacol conjunction) two boron (638mg, 2.51mmol) it is dissolved in DMSO (7.5mL) with potassium acetate, is stirred at room temperature.It is added thereto to compound 3-(4-bromo-2-iodine Phenyl)-2-(tertbutyloxycarbonylamino) propanoic acid tert-butyl ester (1.50g, 2.40mmol) DMSO solution (4.5mL) after, 80 DEG C stirring 24 hours.With ethyl acetate (70mL) diluting reaction solution, after carrying out kieselguhr filtration, clean with water and saline solution, Use MgSO₄It is dried organic layer.Organic layer is filtered, after being concentrated by organic solvent, utilizes column chromatography (hexane: ethyl acetate =9:1) refine, thus obtain the object (705mg, 47%) as colorless oil.

¹H-NMR(CDCl₃)；1.35-1.48(m,39H,pinacol-CH₃× 4, t-Bu), 3.08 (dd, J=11.2, 13.6,1H,CH₂-α), 3.89 (dd, J=4.4,14.0,1H, CH₂-β), 5.17 (dd, J=4.0,11.2,1H, CH), 6.91 (d, J=8.0,1H, Ar), 7.41 (dd, J=2.0,8.0,1H, Ar), 7.89 (d, J=2.0,1H, Ar).

The compound (37.6mg, 0.060mmol) obtained in last operation adds four (pyridine) copper fluoroform sulphonate (3.6mg, 0.0053mmol), adds potassium fluoride (3.8mg, 0.066mmol) and 4 further, 7,13,16,21,24-six oxygen-1, The DMF solution (4mL) of 10-diazabicyclo [8.8.8] hexacosane (24.8mg, 0.066mmol), reacts 20 points at 130 DEG C Clock.Thereafter, after filtration, carry out concentrating under reduced pressure, obtain the mixture containing target compound.

The manufacture of (embodiment 5) 2-fluoro-4-iodine bromobenzyl

By using the method as S-2 operation, obtain target compound 2-fluoro-4-iodine bromobenzyl.

¹H-NMR(CDCl₃)；4.45(s,2H,CH₂), 7.12 (t, J=8.0,1H, Ar), 7.45 (d, J=8.4,1H, Ar), 7.48 (d, J=8.4,1H, Ar).

The manufacture of 3-(2-fluoro-4-iodophenyl)-2-(diphenyl methylene amino) ethyl propionate

By using the method as S-3 operation, substitute N-(diphenyl methylene) glycine benzyl ester and make N-(hexichol Asia Methyl) compound that obtains in glycine ethyl ester and last operation reacts, thus obtains target compound 703.Should illustrate, no Refine and be directly entered next operation.

The manufacture of 2-amino-3-(2-fluoro-4-iodophenyl) ethyl propionate

By using the method as S-4 operation, obtain target compound 704.

¹H-NMR(CDCl₃)；1.24 (t, J=7.2,3H, CH₂ CH ₃), 2.86 (dd, J=8.0,13.6,1H, CH₂-α), 3.04 (dd, J=5.9,14.0,1H, CH₂-β), 3.71 (dd, J=6.0,7.6,1H, CH), 4.16 (q, J=7.2,2H,CH ₂CH₃), 6.95 (t, J=8.0,1H, Ar), 7.40 (d, J=7.6,1H, Ar), 7.42 (d, J=7.6,1H, Ar).

The manufacture of 3-(2-fluoro-4-iodophenyl)-2-(Benzyoxycarbonylamino) ethyl propionate

By using the method as S-5 operation, obtain target compound 705.

¹H-NMR(CDCl₃)；1.24 (t, J=7.3,3H, CH₂ CH ₃), 3.06 (dd, J=6.8,13.6,1H, CH₂-α), 3.16 (dd, J=4.8,14.0,1H, CH₂-β), 4.17 (q, J=7.2,2H,CH ₂CH₃),4.61(m,1H,CH),5.08(m, 2H,CH₂Ar), 5.29 (d, J=8.0,1H, NH), 6.84 (t, J=7.6,1H, Ar), 7.31-7.38 (m, 7H, Ar).

In addition it is possible to use the compound obtained in last operation, make pinacol boronation in the same manner as embodiment 1 or 3 Compound.

The deprotection of the pinacol boronated compound of reference example 1 fluorine labelling

The pinacol boronated compound obtained in embodiment 1～4 can be carried out deprotection respectively, prepare target Fization BPA.Specifically, first, utilize 4N hydrochloric acid-ethyl acetate that Boc and t-Bu is carried out deprotection.

It follows that use 0.1% acetic acidacetonitrile series solvent with reversed-phase column eluting, thus pinacol is also removed, and obtains mesh Mark Fization BPA.

Claims

1. the compound represented by following formula,

Wherein, R¹Represent bromo, iodo, chloro, nitro or amino；R²Represent halogen radical, nitro, amino, Sn (R⁶)₃, N= N-NR⁷R⁸、OSO₂R⁹、NR¹⁰R¹¹, replace or unsubstituted phenyl-iodide, replacement or unsubstituted heterocyclic radical iodine or boric acid i.e. B (OH)₂Or borate, this borate selected from pinacol, 2，2-dimethyl-1，3-propanediol, N methyldiethanol amine, 1,8-bis- Any one in amino naphthalenes, N-methyliminodiacetic acid, 1,1,1-trihydroxy methyl ethane and catechol；Wherein, R⁶Represent The alkyl of carbon number 1～7 or benzyl；R⁷And R⁸Represent identical or differently hydrogen, the alkyl of carbon number 1～7, by halogen The alkyl of substituted carbon number 1～7, any substituted phenyl, or form the ring knot with 3～7 atoms together with N Structure；R⁹The alkyl representing carbon number 1～7, the alkyl of carbon number 1～7 being optionally substituted by halogen or any substituted benzene Base；R¹⁰And R¹¹The alkyl that represents carbon number 1～7 identical or differently, the alkyl of the carbon number 1～7 being optionally substituted by halogen, Any substituted phenyl, or form the ring structure with 3～7 atoms together with N；R³Represent hydrogen, ethyl, the tert-butyl group or Person's benzyl, R⁴Or R⁵Represent hydrogen, benzyloxycarbonyl or tert-butoxycarbonyl, or NR independently⁴R⁵Overall expression C₆H₅ (C₆H₅) C=N,

Wherein, following situation is not included:

1)R³、R⁴And R⁵All hydrogen, and R²Situation for chloro；

2)R³、R⁴And R⁵All hydrogen, R²For bromo, and R¹For the situation of any one in bromo, chloro, nitro or amino；

3)R³、R⁴And R⁵All hydrogen, R²For iodo, and R¹For the situation of any one in chloro or nitro；

4)R³For hydrogen, R²For chloro, and R¹For in chloro, bromo or nitro any one, R⁴Or R⁵In any one is the feelings of hydrogen Condition；

6)R⁴And R⁵For hydrogen, R²For chloro, and R¹Situation for nitro；

8)R¹For chloro, R²For fluorine-based, R⁴And R⁵For hydrogen, and R³Situation for ethyl.

Compound the most according to claim 1, wherein, R¹Represent bromo, iodo, chloro, nitro or amino；R²Represent Halogen radical, nitro, amino, Sn (R⁶)₃, N=N-NR⁷R⁸、OSO₂R⁹、NR¹⁰R¹¹, replace or unsubstituted phenyl-iodide, replacement or nothing Substituted heterocyclic radical iodine or boric acid i.e. B (OH)₂Or borate, this borate selected from pinacol, 2,2-dimethyl-1,3-third Glycol, N methyldiethanol amine, 1,8-diaminonaphthalene, N-methyliminodiacetic acid, 1,1,1-trihydroxy methyl ethane and youngster Any one in tea phenol；Wherein, R⁶Represent alkyl or benzyl, the R of carbon number 1～7⁷And R⁸Represent identical or differently hydrogen, The alkyl of carbon number 1～7, the alkyl of carbon number 1～7 being optionally substituted by halogen, any substituted phenyl, or together with N Form the ring structure with 3～7 atoms；R⁹The alkyl representing carbon number 1～7, the carbon number 1～7 being optionally substituted by halogen Alkyl or any substituted phenyl；R¹⁰And R¹¹Represent the alkyl of carbon number 1～7 identical or differently, taken by halogen The alkyl of the carbon number 1～7 in generation, any substituted phenyl, or form the ring structure with 3～7 atoms together with N； Wherein, R¹And R²In either one is necessary for bromo, iodo or chloro；R³Represent hydrogen, ethyl, the tert-butyl group or benzyl； R⁴Or R⁵Represent hydrogen, benzyloxycarbonyl or tert-butoxycarbonyl, or NR independently⁴R⁵Overall expression C₆H₅(C₆H₅) C= N,

Wherein, following situation is not included:

1)R³、R⁴And R⁵All hydrogen, and R²Situation for chloro；

6)R⁴And R⁵For hydrogen, R²For chloro, and R¹Situation for nitro；

Compound the most according to claim 2, wherein, R¹Represent bromo, iodo, chloro, nitro or amino；R²Represent Halogen radical, nitro, amino, Sn (R⁶)₃, N=N-NR⁷R⁸、OSO₂R⁹、NR¹⁰R¹¹, replace or unsubstituted phenyl-iodide, replacement or nothing Substituted heterocyclic radical iodine or boric acid i.e. B (OH)₂Or borate, this borate selected from pinacol, 2,2-dimethyl-1,3-third Glycol, N methyldiethanol amine, 1,8-diaminonaphthalene, N-methyliminodiacetic acid, 1,1,1-trihydroxy methyl ethane and youngster Any one in tea phenol；Wherein, R⁶Represent alkyl or benzyl, the R of carbon number 1～7⁷And R⁸Represent identical or differently hydrogen, The alkyl of carbon number 1～7, the alkyl of carbon number 1～7 being optionally substituted by halogen, any substituted phenyl, or together with N Form the ring structure with 3～7 atoms；R⁹The alkyl representing carbon number 1～7, the carbon number 1～7 being optionally substituted by halogen Alkyl or any substituted phenyl；R¹⁰And R¹¹Represent the alkyl of carbon number 1～7 identical or differently, taken by halogen The alkyl of the carbon number 1～7 in generation, any substituted phenyl, or form the ring structure with 3～7 atoms together with N； Wherein, R¹And R²In either one is necessary for bromo, iodo or chloro；R³Represent hydrogen, ethyl, the tert-butyl group or benzyl； R⁴Or R⁵Represent hydrogen, benzyloxycarbonyl or tert-butoxycarbonyl, or NR independently⁴R⁵Overall expression C₆H₅(C₆H₅) C= N,

Wherein, following situation is not included:

1)R³、R⁴And R⁵All hydrogen, and R²Situation for chloro；

5)R³For hydrogen, R²For bromo, and R¹Situation for chloro；

6)R⁴And R⁵For hydrogen, R²For chloro, and R¹Situation for nitro；

4. according to 1 described compound wantonly in claims 1 to 3, wherein, R¹Represent bromo, iodo, chloro, nitro or Amino, R²Represent halogen radical, nitro, amino, Sn (R⁶)₃, N=N-NR⁷R⁸、OSO₂R⁹、NR¹⁰R¹¹、I⁺R¹³、(R^14-)I⁺R¹³, or Boric acid or borate, this borate selected from pinacol, 2，2-dimethyl-1，3-propanediol, N methyldiethanol amine, 1,8-diamino Any one in base naphthalene, N-methyliminodiacetic acid, 1,1,1-trihydroxy methyl ethane and catechol；Wherein, R⁶Represent first Base or normal-butyl；R⁷And R⁸Represent hydrogen, methyl, ethyl, propyl group, butyl, heptyl, trifluoromethyl identical or differently or appoint Anticipate substituted phenyl, or form aziridine, azetidine, pyrrolidine, piperidines together with N；R⁹Represent methyl, second Base, propyl group, butyl, heptyl, trifluoromethyl or any substituted phenyl；R¹⁰And R¹¹Represent methyl, second identical or differently Base, propyl group, butyl, heptyl, trifluoromethyl or any substituted phenyl, or form aziridine, azepine together with N Tetramethylene., pyrrolidine, piperidines；R¹³Represent C_1-6Alkyl-substituted phenyl, C_1-6Alkoxy substituted phenyl or phenyl or represent Containing 1 in N, S or O or 5～7 yuan of heterocyclic radicals of more than 2；R¹⁴Represent halogen, Tetrafluoroboric acid alkali, nitrate-based, three Fluorine methanesulfonate-based, sulfonyloxy, tosyloxy or perchloric acid alkali；Wherein, R¹And R²In either one is necessary For bromo, iodo or chloro；R³Represent hydrogen, ethyl, the tert-butyl group or benzyl, R⁴Represent hydrogen, R⁵Represent hydrogen, benzyloxy carbonyl Base or tert-butoxycarbonyl, or NR⁴R⁵Overall expression C₆H₅(C₆H₅) C=N.

5. according to 1 described compound wantonly in claims 1 to 3, wherein, R¹Represent bromo, iodo or chloro, R²Represent Sn(R⁶)₃, N=N-NR⁷R⁸、OSO₂R⁹、NR¹⁰R¹¹、I⁺R¹³、(R^14-)I⁺R¹³, or boric acid or pinacol, 2,2-dimethyl-1, Ammediol, N methyldiethanol amine, 1,8-diaminonaphthalene, N-methyliminodiacetic acid, 1,1,1-trihydroxy methyl ethane, Any one in catechol.

6. according to 1 described compound wantonly in claims 1 to 3, wherein, R²For iodo or bromo.

7. a manufacture method for the compound that following formula represents,

Wherein, X represent F or¹⁸F；R³⁰Represent hydrogen or the blocking group PG of carboxyl¹, R⁴⁰Or R⁵⁰Independently represent hydrogen or The blocking group PG of amino², or NR⁴⁰R⁵⁰Overall expression C₆H₅(C₆H₅) C=N；R¹⁵And R¹⁶Together form with the i.e. boron atom of B As the ring of the blocking group of B,

Described manufacture method includes the operation of the compound using following formula to represent,

Wherein, R¹Represent bromo, iodo, chloro, nitro or amino；R²Represent halogen radical, nitro, amino, Sn (R⁶)₃, N= N-NR⁷R⁸、OSO₂R⁹、NR¹⁰R¹¹, replace or unsubstituted phenyl-iodide, replacement or unsubstituted heterocyclic radical iodine or boric acid or boron Any one in acid esters；Wherein, R⁶Represent alkyl or the benzyl of carbon number 1～7；R⁷And R⁸Represent identical or differently hydrogen, The alkyl of carbon number 1～7, the alkyl of carbon number 1～7 being optionally substituted by halogen, any substituted phenyl, or together with N Form the ring structure with 3～7 atoms；R⁹The alkyl representing carbon number 1～7, the carbon number 1～7 being optionally substituted by halogen Alkyl or the phenyl that is optionally substituted；R¹⁰And R¹¹Represent the alkyl of carbon number 1～7, by halogen identical or differently The alkyl of substituted carbon number 1～7, the phenyl being optionally substituted, or form the ring knot with 3～7 atoms together with N Structure；R³⁰、R⁴⁰And R⁵⁰Same as described above.

8. one kind¹⁸The manufacture method of F labelling BPA, including the operation of the compound using following formula to represent,

Wherein, X represent F or¹⁸F；R³⁰Represent hydrogen or the blocking group PG of carboxyl¹, R⁴⁰Or R⁵⁰Independently represent hydrogen or The blocking group PG of amino², or NR⁴⁰R⁵⁰Overall expression C₆H₅(C₆H₅) C=N；R¹⁵And R¹⁶Together form with the i.e. boron atom of B Ring as the blocking group of B.